Molecular recognition of naphthoquinone-containing compounds against human DNA topoisomerase IIα ATPase domain: A molecular modeling study Panupong Mahalapbutr a , Phakawat Chusuth a , Nawee Kungwan b,c , Warinthorn Chavasiri d , Peter Wolschann a,e,f , Thanyada Rungrotmongkol a,g, ⁎ a Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand b Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand c Research Center on Chemistry for Development of Health Promoting Products from Northern Resources, Chiang Mai University, Chiang Mai 50200, Thailand d Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand e Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna 1090, Austria f Institute of Theoretical Chemistry, University of Vienna, Vienna 1090, Austria g Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand abstract article info Article history: Received 6 September 2017 Received in revised form 30 September 2017 Accepted 3 October 2017 Available online 04 October 2017 Several quinone-based metabolites of anticancer drugs and naturally occurring quinone-containing compounds have been characterized as potent inhibitors toward topoisomerase IIα (TopoIIα), an essential enzyme involved in maintaining genomic integrity during DNA replication and mitotic division. Mansonone G (MG), a naphthoquinone-containing compound extracted from the heartwood of Mansonia gagei, exhibits various biolog- ical activities including antitumor potential. In the present study, MG and its semi-synthetic derivatives were se- lected to study the preferential binding site and dynamics behavior as well as to predict the inhibitory activity against TopoIIα using molecular modeling approaches. The molecular docking results revealed that the entire se- ries of MG preferentially target to the ATPase domain. Among all studied MGs, the ester derivative MG14 contain- ing C-10 length exhibited the highest binding affinity against TopoIIα and greater than that of the ATP- competitive inhibitor salvicine as well as 1,4-benzoquinone. Interestingly, the MG14 binding could induce the closed form of the turn region (residues 147–151) inside ATP-binding pocket, implying that this event might be one of the crucial mechanisms underlying TopoIIα inhibition. The obtained theoretical information is useful as rational guide for further development of new anticancer agents containing naphthoquinone moiety against TopoIIα. © 2017 Elsevier B.V. All rights reserved. Keywords: DNA topoisomerase II Mansonone G Computational simulation 1. Introduction DNA topoisomerase II (TopoII, Fig. 1A) is a nuclear enzyme that plays an important role in a number of DNA-related processes such as replica- tion, transcription, recombination, and mitosis [1–3]. To maintain geno- mic integrity during such events, TopoII alleviates the topological constraints of the genetic material by breaking and rejoining the phos- phodiester backbone of undesirable regions (i.e., superhelical twists, tangles, and knots) using double-stranded break mechanism [4]. TopoII is a homodimeric enzyme with two catalytically important domains: (i) the N-terminal ATPase domain, which catalyses the hydrolysis of ATP molecules, providing the energy for catalytic processes and (ii) the cen- tral domain, which is located at the center of cleavage/religation do- main, comprising the important catalytic residues (TOPRIM sequence and Tyr805) for DNA breaking and resealing (Fig. 1D) [5]. Mammals have two closely related TopoII isoforms, TopoIIα and TopoIIβ, that share 93% of similarity and 81% of identity for their ATPase and cleav- age/religation domains [2]. The expression level of TopoIIβ remains con- stant throughout the cell cycle, whereas TopoIIα is expressed at high levels and dramatically increased during G2/M phase of the cancer cell cycle, making it an ideal protein target for molecularly targeted therapy [2,6,7]. There are two classes of TopoII-targeting compounds: (i) TopoII poisons (i.e., etoposide (VP-16), teniposide (VM-26), doxorubicin, amsacrine and mitoxanthrone) [8], which can target the catalytic core domain or stabilize the enzyme-DNA complex (known as cleavage com- plex) [9–11], resulting in DNA strand breaks and (ii) TopoII catalytic in- hibitors (i.e., ICRF-193 [12], novobiocin [13], sobuzoxane (MST-16) [14], Journal of Molecular Liquids 247 (2017) 374–385 ⁎ Corresponding author at: Structural and Computational Biology Research Group, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Bangkok 10330, Thailand. E-mail address: thanyada.r@chula.ac.th (T. Rungrotmongkol). https://doi.org/10.1016/j.molliq.2017.10.021 0167-7322/© 2017 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq